Macrophages have been implicated as target cells and disseminators of viral infection. Macrophages isolated from genetically resistant mouse strains defend against infection with Herpes Simplex Virus (HSV) by inhibiting replication. HSV does not replicate well in human blood monocytes, probably due to similar mechanisms. The proposed investigations are designed to characterize the interaction of HSV with macrophages of different genetic backgrounds and of different tissue origins, utilizing the following approaches: 1. Macrophages (from bone marrow, spleen, liver, peritoneum and lung) from susceptible and resistant inbred strains of mice, AND human peripheral blood monocytes will be examined for ability to support or inhibit HSV replication in culture. Specifically, we will examine: a) viral entry (adsorption/penetration) b) macromolecular synthesis c) virion assembly 2. The effects of anti-viral factors which are known to inhibit viral replication (Interferon, Tumor Necrosis Factor, defensins) will be examined in: a) HSV-infected mouse macrophages or cell lines from susceptible and resistant mouse strains; b) HSV-infected human peripheral monocytes and macrophage cell lines. 3. HSV genetic variants which replicate efficiently in mouse macrophages (susceptible and resistant) will be selected. The effects of these genetic variants on LD50 in mice will be compared to those observed with parental virus. Information obtained from these studies will further knowledge of how macrophages defend against viral infection and how viruses circumvent these macrophage defense systems. In addition, the proposed studies with anti-viral factors will aid in defining the genes or gene products which render resistance to HSV disease.